Gunji K, De Bellis A, Kubota S, Swanson J, Wengrowicz S, Cochran B, Ackrell B A, Salvi M, Bellastella A, Bizzarro A, Sinisi A A, Wall J R
Department of Medicine, Allegheny University Hospitals, Allegheny General, Pittsburgh, Pennsylvania 15212-4772, USA.
J Clin Endocrinol Metab. 1999 Apr;84(4):1255-62. doi: 10.1210/jcem.84.4.5640.
Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves' hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves' hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism.
甲状腺相关眼病是一种眼外肌和眼眶结缔组织的自身免疫性疾病，通常与格雷夫斯甲亢相关。经过充分研究的眼病标志物是眼肌膜抗原，据报道其分子量约为64 kDa。其中一种最初仅被鉴定为64 kDa蛋白，最近已被证明是线粒体琥珀酸脱氢酶的黄素蛋白（Fp）亚基，其正确分子量为67 kDa。我们已将纯化的牛心Fp用作抗原，进行酶联免疫吸附测定以检测交叉反应性人类自身抗体。已对根据活动情况以及是否存在眼肌疾病进行分类的甲状腺相关眼病患者的血清进行了筛查，也对无眼部受累的格雷夫斯甲亢患者的血清进行了筛查。还检查了20例格雷夫斯甲亢患者在使用抗甲状腺药物治疗甲亢的24个月期间定期采集的血清样本。这些患者中，4例在发病时患有眼病，12例在治疗过程中出现眼病，4例在治疗期间未出现任何眼部体征。在有活动性眼病且有眼肌受累证据的患者中，73%检测到抗Fp亚基抗体，但如果仅有充血性眼病，则只有25%检测到。对于有或无眼肌功能障碍的慢性眼病患者，这些值分别为0%和11%。在无明显眼病的格雷夫斯甲亢患者中，14%检测到抗体，在非免疫性甲状腺疾病患者中，11%检测到抗体，在I型糖尿病患者中，12%检测到抗体，在年龄和性别匹配的正常受试者中，12%检测到抗体。值得注意的是，抗Fp抗体的出现预测了6例格雷夫斯甲亢患者中有五例发生眼病，这五例患者在甲亢治疗后出现了眼肌功能障碍，另一例患者的抗体出现与眼肌体征的出现同时发生。在6例出现充血性眼病但无眼肌损伤证据的患者以及4例未出现任何眼部体征的患者中，均未检测到抗体。总之，我们已经证明格雷夫斯甲亢患者的眼肌疾病与抗琥珀酸脱氢酶Fp亚基的血清抗体之间存在密切关系。
